Abstract Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations (AVMs) in the brain, lung and liver, causing life-threatening hemorrhage, stroke, and heart failure. Intracranial hemorrhage (ICH) from brain AVMs (BAVMs) is the most feared complication and remains a therapeutic and prevention challenge. Available treatment modalities for BAVMs are invasive and their associated morbidity must be weighed against ICH risk. Though the mean rate of ICH from BAVMs in HHT is relatively low, the distribution is wide, with a large range of risk. As such, clinical decisions for individual patients require weighing the morbidity of treatment against the risk of poor outcomes, including ICH and neurologic disability from BAVMs. Our first overarching goal is thus to identify BAVM patients at high risk of poor outcomes to help guide clinical decision-making in individuals. We also propose to extend our measurement of AVM bleeding risk in HHT to include the much more common bleeding phenotype in HHT, chronic nasal bleeding, as we hypothesize that there are shared predictors of bleeding across affected organs in HHT. Specifically, we will define the severe nasal bleeding phenotype (patient reported outcome, PRO) and measure biomarkers, genetic modifiers and clinical predictors of bleeding severity. Several molecular pathways have been linked to HHT and there has been a recent explosion of potential pharmacologic therapies for HHT and AVMs, including anti-angiogenic, anti-inflammatory, immune modulating agents, and others. As the safety and benefits of these therapies are assessed through trials for chronic bleeding in HHT, trials for BAVM treatment in HHT become more plausible. We plan to establish clinical trial readiness for HHT and BAVM, through development of bleeding severity measures and comprehensive brain outcomes measures. We propose to leverage our established recruitment network, our large HHT cohort (N=2400, including 600 with BAVM, by end of Cycle 3), and progress made in the first two cycles characterizing genetic and clinical predictors, to accomplish the following specific aims: (Aim 1) to identify predictors of brain outcomes in HHT patients; (Aim 2) to define a severe bleeding phenotype in HHT for clinical trial readiness; and (Aim 3) to identify genetic predictors and circulating biomarkers of severe bleeding and brain outcomes in HHT. Project 3 participants will be recruited through 16 HHT Treatment Centers and through the Patient Advocacy Group (HHT Foundation International, CureHHT). The HHT investigator group will continue to work closely with the HHTFI, as well as with the DMCC, leveraging the established DMCC web-based portal, data collection and management protocols in place. The combined output of all three Aims will help guide clinical decision making for BAVM patients and will poise the HHT scientific community to undertake clinical trials of newly available pharmaco-therapies, in patients with HHT and BAVMs.